Osteoporosis is a major bone disorder that affects both men and women during aging. The pathogenesis is not only due to the increased osteoclast activity in bone resorption, but also a decrease in bone formation mostly attributed to an insufficient supply of osteoblasts in the aged. Osteoblasts are non-replicative cells derived from the mesenchymal stem cell (MSC) lineage. We hypothesize that the pattern of acquisition of bone mass during childhood, maintenance in adulthood, and loss with aging is due to decreased osteoblast availability for bone formation as MSCs lose/slow their ability to differentiate into osteoblasts with aging. Insulin like growth factor type 1 (IGF-1) is known to stimulate osteoblastic differentiation by activation of mammalian target of rapamycin to maintain proper bone microarchitecture and mass. Thus, a series of experiments and animal models are designed to confirm the hypothesis that MSC differentiation slows with aging, mediated by down- regulation of the IGF-1 signaling pathway. The first aim is to determine the temporal-spatial regulation of MSC differentiation into mature osteoblasts in young, adult, and old mice using a MSC lineage tracing mouse model. The second aim is to dissect how the IGF-1 signaling pathway is regulated during the lifespan and affects the fate of MSCs. The goal of the proposed study is to identify the rate limiting steps in the differentiation process so that future therapies can be targeted at these essential steps. This project will be conducted by Dr. Janet Crane under the guidance of Dr. Xu Cao in the Department of Orthopaedic Surgery at Johns Hopkins University. Dr. Crane, a Pediatric Endocrinologist, is dedicated to a career in academia using basic and translational research to study factors affecting bone formation. Dr. Cao has an exceptional research career in bone biology using in vivo mouse models to study signaling mechanisms by which bone marrow MSCs contribute to bone homeostasis and remodeling, which will provide Dr. Crane with the training necessary to initiate her career as an independent investigator. The available resources and strong ongoing collaborative arrangements within the Department of Orthopaedic Surgery, the Division of Pediatric Endocrinology, and the Department of Neuroscience provide a rich learning environment and are completely supportive of the academic advancement of Dr. Crane.